Familial hypercholesterolemia resulting from mutations in the LDL receptor gene is a disease that appears 1 out of 500 people (250000 people domestically), and is the most common disease among the hereditary metabolic disorders. Patients' serum total cholesterol levels show 230 to 500 mg/dL (healthy person: 200 mg/dl or less), and symptoms such as xanthoma of the skin and tendon and coronary artery disease resulting from juvenile arteriosclerosis are observed. The average life expectancy of the patients is 54 years for male and 69 years for female, being much shorter than the average life expectancy of the entire population. A typical therapeutic method may be LDL apheresis treatment, but this therapeutic method is problematic in that the method imposes a large burden on the patient. An example of drug therapy may be administration of statins, but there is a problem in that statins do not show sufficient effects on familial hypercholesterolemia.
Meanwhile, hyperlipidemia is a lifestyle-induced disease that causes cardiac infarction and apoplexy, which are causes of death next to cancer.
In therapeutic development for such hypercholesterolemia, a strategy targeting PCSK9, which regulates the metabolism of an LDL (low-density lipoprotein) receptor, has recently been attracting attention (Non Patent Literature 1). It aims at lowering the blood LDL concentration by suppressing the expression of the PCSK9 gene, which decomposes the LDL receptor, and thus increasing the level of LDL receptor expression and facilitating the cellular uptake and metabolism of LDL. Therapeutic experiments using an antisense method that is one technique involving nucleic acid medicines are also in progress.
Most of the conventional nucleic acid medicines that are effective in the in vitro cellular system are, however, not effective in vivo. Possible causes may be that conventional nucleic acid medicines are immediately decomposed when introduced into the body and that the affinity and specificity of conventional nucleic acid medicines to the target gene are poor, and therefore an antisense technique has been attracting attention as a technique to suppress the PCSK9 gene expression.
The 2′-MOE (2′-O-methoxyethyl)-modified oligonucleotide described in Non Patent Literature 2 has excellent stability in the living body but has a poor binding affinity to the target RNA, and is thus problematic in that a very high dose is required to demonstrate a pharmaceutical effect. The oligonucleotide containing a locked nucleic acid (LNA) described in Non Patent Literature 1 has a superior binding affinity to the target RNA, and an effect of suppressing the mRNA of PCSK9 in vivo also is shown, but there is still room for improvement in stability, safety, and the like in the living body.